Human Papillomavirus Vaccination

American College of Pediatricians, January 2016

Human papillomavirus (HPV) is a prevalent sexually transmitted virus, approximately 14 types of which can cause multiple cancers. The most common HPV-induced malignancy by far is cervical cancer which claims about 4,000 lives in the U.S. yearly. Three vaccines licensed since 2006 have generally been found to be safe and effective. They could potentially prevent the vast majority of HPV-induced cancers. Healthcare providers should also strive to promote sexual fidelity which could prevent not only HPV problems but other sexually transmitted infections and unwanted pregnancies.

Disease and Vaccine Background

Human papillomavirus (HPV) is the most common cause of new sexually transmitted infections (STIs) in the U.S.1 HPV causes common warts, anal and genital warts, growths on babies’ vocal cords and other areas of their respiratory tracts, and multiple cancers including those involving the uterine cervix, mouth and throat (oropharyngeal), anal, and genital organs.2,3 About 40 of the over 100 strains or types are spread sexually.4 At least 13 of these sexually transmitted types can cause cancer.5 Consequently, over the past 40 years, as increasing numbers of adolescents and adults have engaged in oral sex with multiple partners, oropharyngeal cancer caused by HPV has also increased.6 Cervical cancer, however, is by far the most common form of cancer caused by HPV with over 12,000 new cases and about 4,000 deaths in the United States yearly, despite Pap smear screening which greatly limits the number of potential cases that go on to an invasive cancer.7 Cervical cancer requires a chronic HPV infection that manifests as cervical intraepithelial neoplasia (CIN) years prior to developing into cervical cancer.8 There are nearly 2.8 million abnormal Pap smears per year in the U.S.6 which have been very helpful in identifying CIN, allowing treatment to prevent most cases of potential cancer. That treatment is costly and burdensome, and many women, especially in other countries around the world, do not get the needed screening for cancer prevention.2,9

The first vaccine against HPV, Gardasil®, was introduced in 2006 for females and in 2009 for males.2 It contains immunity-inducing parts of four HPV types; 6, 11, 16 and 18, and is referred to as HPV4. Types 6 and 11 cause at least 90% of anogenital warts,4 while type 16 is detected in about 90% of HPV-positive oropharyngeal cancers7 and is the most common type to cause cervical cancer. Exposure to any of those four types as determined by seroprevalence (proportion of individuals with significant antibody levels) was as high as 42% in women aged 30 to 39 years and up to 18% in men aged 50-59 years based on a large U.S. study involving over 4,000 subjects in 2003-2004.4 Antibody levels were not found to fall with increasing age, but women older than 38 in England had lower seroprevalence to types 16 and 18, presumably reflecting a change in sexual behavior in recent decades.10 Exposure rates are significantly higher than seroprevalence rates because males more than females, frequently do not make detectable antibodies when infected. Exposure is influenced by number of sexual partners. For type 16, seroprevalence ranges from 5% in the general male population,4 to 12% in a population of sexually active males in Tucson, Arizona and Tampa, Florida,5 and up to 48% in sexually transmitted disease clinics.11 The 48% seroprevalence was found in those who tested HIV negative at a clinic testing men who had sex with men for HIV and HPV types 6, 11 and 16. A large (over 2,000 women ages 14 to 59) U.S. study3 looking at prevalence of infection by polymerase chain reaction (PCR) testing found type 16 in 1.5%, type 18 in 0.8%, and any of the HPV4 types in 3.4% of participants. Overall “HPV prevalence” (looking for 27 to 37 strains, 20 of which were considered low-risk types) was 26.8%. That was influenced by age; 24.5% for ages 14-19 years, 44.8% in 20-24 year-olds, 27.4% in 25-29 year-olds, 27.5% in 30-39 year-olds, 25.2% in 40-49 year-olds, and 19.6% in 50-59 year-olds.

Another vaccine, CervarixTM, was released in the U.S. in 2009 containing only strains 16 and 18 (HPV2).12 Those two strains together cause about 66% of cervical cancers.13 At the end of 2014, the FDA approved a 9-strain (HPV9) vaccine, Gardasil-9®, which includes strains 6, 11, 16, 18, 31, 33, 45, 52, and 58. The last 5 strains added to HPV9 are high-risk strains responsible for about 15% of cervical cancers,13 but HPV9 may protect against about 90% of potential cervical cancer.14 There is a role of cross-protection between strains, so even HPV2 may protect against more than 66% of cervical cancers including, to varying degrees, those caused by the extra five strains included in HPV9.9,15

Effectiveness

Both original HPV vaccines (HPV4 and HPV2) have made a significant impact on sexually spread HPV. Protection against complications like cervical dysplasia has been demonstrated, but is very limited if infection is acquired prior to vaccination.8 A new vaccine is being tested that is showing some promise in reversing some HPV-induced cervical neoplasia.16 HPV2 showed protection against both oral and cervical infections with HPV types 16 and 18 over a four year follow-up in Costa Rica.7 In a 14-16 year-old sexually active Dutch population, HPV2 has also had excellent protection against new and prolonged (at least 6 months) infections with types 16 and 18, and there was some protection against infection with other strains.17 HPV2 compared to hepatitis A controls was also found to be protective in Japan against CIN after several years of follow-up.9 HPV4 use in Denmark has been associated with a significant decrease in cervical atypia and CIN in 18-20 year olds but not in older women (as expected since they did not have the benefit of the vaccine).18 HPV9 has likewise shown high (96.6%) efficacy against high-grade genital lesions and a 96.0% reduction in persistent infections associated with the 5 added strains in vaccinated girls.14 High-grade cervical lesions declined (statistically significant in ages 21-24) in Connecticut from 2008 to 2011 as HPV vaccine use increased from 45% to 61%.19 Despite high expectancy of effectiveness, HPV vaccines are not 100% effective and follow-up exams and Pap smears will still be recommended, although the recommended frequency of Pap smears may be decreased.14 Three doses of each HPV vaccine are still recommended, but there is some evidence that 2 doses of HPV2 may be effective.20 Ongoing studies are examining that possibility.

Longer follow-up studies will be more revealing regarding long-term protection for children who may be vaccinated a decade or more before the onset of sexual activity, but antibody titers sustained up to 9 years after HPV2 administration indicate that long-term protection is likely for that vaccine.21 Another factor in favor of long-term protection is the robust immune memory demonstrated (also with HPV2) with later booster doses.8 Antibody levels after complete HPV9 series were significantly higher in recipients aged 9 through 15 years compared with females aged 16 through 26 years.13 This observation, in addition to the limited effectiveness of the vaccine after HPV exposure, supports vaccinating at a younger age.

Serology studies looking at protection after receiving multiple simultaneous vaccines such as Menactra® and Tdap along with HPV9 have found no detectable interference among the different vaccines.13

Comparing efficacy of HPV2 versus HPV4 or HPV9 is somewhat difficult. While the latter two vaccines are likely to give significantly better protection against genital warts, and HPV9 contains five extra high cancer-risk strains, HPV2 has been shown to give superior immunologic responses and actually has shown somewhat better protection against CIN due to all HPV types.12 Likewise, HPV2 has shown efficacy with 1 or 2 doses.20

Safety

There were extensive safety trials before licensure of HPV4, HPV2 and HPV9. No significant concerns were found then or even in post-licensure studies.22 There was a higher rate of local reactions and syncope after HPV4, so patients receiving these vaccines should be monitored after injection for about 15 minutes while sitting or lying.22 Local reaction rates were about 10% higher in HPV9 than in HPV4 female (but not male) recipients.13 Potential adverse events including adverse pregnancy outcomes, autoimmune conditions, demyelinating and other neurological conditions, anaphylaxis, thromboembolic problems, and stroke have been studied.22-25 Post-vaccine rates have not been found to be different from background rates. The use of HPV vaccines in girls and women with special problems such as human immunodeficiency virus infections and systemic lupus erythematosus has also (with more limited study numbers) been found to be safe and effective.22 In a large Scandinavian study,24 only three of 23 autoimmune events had significant association with HPV vaccination; Behcet’s syndrome, Raynauld’s disease, and type 1 diabetes. There was no association between venous thromboembolism and vaccine exposure and there were inverse associations with epilepsy. On further assessment, the three conditions with significant associations were weak associations not temporally related to vaccine exposure.

The debate as to whether vaccinating adolescents against a sexually transmitted infection such as HPV may contribute to an increase in premarital sex is not settled. A large study examining health claims from 41 large employers across the U.S. found that sexually transmitted infection rates were higher in the year following vaccination (6.8 per 1000) than that found in unvaccinated controls over the same year (4.2 per 1000), but there was not any significant difference in the increases from before to after vaccination.26 The vaccinated group had higher rates before vaccination. The vaccinated group rate (per 1000) went from 4.3 to 6.8 (58% increase) while the unvaccinated group rate went from 2.8 to 4.2 (50% increase). The unvaccinated group rate one year later still was slightly lower than the beginning rate of the vaccinated group. Another study purported to show no increase in sexual activity in 11-12 year-old girls vaccinated against HPV versus controls vaccinated with other vaccines in the absence of HPV vaccination.27 Their incidence rates for chlamydia testing were 2.20 vs. 1.50, pregnancy testing 4.32 vs. 3.02, pregnancy diagnosis 0.17 vs. 0.10, and counseling on contraceptives (excluding those with dysmenorrhea or acne) 1.39 vs. 0.50 in the HPV vaccine group vs. the control group. The study authors found “slightly, but not significantly, increased contraceptive counseling among HPV vaccine-exposed girls.” This difference however is nearly 3-fold. Another study from the Netherlands noted a significantly (p < 0.002) greater increase over time in the number of 14-16 year old girls that ever had sex in the vaccinated versus unvaccinated groups.17 Overall data is inconclusive at this time and further study is indicated. Whether or not the HPV vaccines are administered to preadolescent or adolescent girls, they need to be counseled regarding the real risks of pre- or extra-marital sex. In the absence of that health-risk behavior, there would be no sexually transmitted infections or HPV-induced cervical cancer. For other information about benefits of abstinence before marriage, see the statement by the American College of Pediatricians on Abstinence Education.

Vaccination against HPV is not recommended during pregnancy in the absence of adequate well-controlled safety studies. In a passive surveillance study of women exposed to HPV4 during pregnancy, with 2,802 enrolled between 2006 and 2012, an analysis from the first two years after licensure of HPV4 did not support a causal role between that vaccine and birth defects or other adverse pregnancy outcomes.22 Ongoing assessments are further examining that issue.

The U.S. maintains a passive reporting system of possible adverse events associated with vaccines called the Vaccine Adverse Event Reporting System (VAERS). In a recent review of 25,176 such events in females after receiving HPV4 between June 2006 and March 2014, “no previously reported or new medical conditions were identified as safety signals which would require further evaluation.”22 There have been recent peer-reviewed case reports28,29 describing 6 cases of premature ovarian failure following receipt of HPV4. The College conducted a search of the VAERS WONDER database and found 12 cases of premature ovarian failure/premature menopause plus 77 cases since 2005 of amenorrhea of at least 4 months duration. HPV4 was associated with 86 of those cases, and HPV2 with 3. None of those cases were associated with any other single vaccine type. See the statement by the American College of Pediatricians, New Concerns about the Human Papillomavirus Vaccine. The College has asked the FDA and the ACIP to review this potential safety concern.

Recommendations

Given the effectiveness of these vaccines against HPV infection and its morbidities, the American College of Pediatricians favors offering HPV vaccination to all children and young adults even if they are committed to abstinence until marriage. Although abstinence outside of marriage is very effective in preventing all types of STIs, there are potential risk circumstances beyond an individual’s control, including sexual assault and the infection of one’s future spouse. Parents should closely monitor their children’s activities while reinforcing both morally and medically sound values. If parents do not model sexual fidelity or fail to restrict their children’s exposure to sexually explicit media, including pornography, then they can expect their children to be at high risk for STI acquisition, and those children should not wait to be vaccinated against HPV. Also, parents should consider that many adolescents will be involved in high-risk activities without their knowledge, and waiting until this is realized may place the child at risk for acquiring HPV. However, the College maintains that use of HPV vaccines should not be mandated by regulatory authorities, but remain a personal decision by parents and their children.

The College is opposed to any legislation which requires HPV vaccination for school attendance. Excluding children from school over refusal to vaccinate for a disease spread only by sexual intercourse is a serious, precedent-setting action that trespasses on the right of parents to make medical decisions for their children. Mandating vaccination as early as 9 years of age places the medical provider in an ethical dilemma. The administration of the vaccine requires explanation to both the parent and the child. Parents may have chosen not to introduce the subject of sexual activity to their preteen children due to their physical and emotional immaturity. Most 9-12 year old children are not sexually active, and many have not entered puberty. Forcing a parent to abandon his/her better judgment and discuss this information with the child would be inappropriate and unnecessarily intrusive.

HPV vaccines are approved for use down to 9 years of age in both males and females. For greatest impact, individuals should be vaccinated before sexual exposure to the virus. While up to 9 years sero-protection has been demonstrated with HPV-2, that data is not available for the more commonly (in the U.S.) used HPV4 or now, HPV9. Therefore, timing of administration is complicated by the uncertainties of both exposure risks and sustained vaccination benefits.

Choice of HPV vaccine could be influenced by potential benefit of HPV9 for the two strains responsible for most genital warts as well as the five additional high-risk strains that raise the expected efficacy against cervical cancer to 90%. On the other hand, HPV2 may still prove to be at least as effective against cervical cancer due to enhanced immune responses and different strain cross-protection. Furthermore, there are no case reports of ovarian failure related to HPV2 and no significant VAERS data linking HPV2 to amenorrhea, unlike HPV4, the predecessor of HPV9.

In conclusion, the American College of Pediatricians recommends that parents use the availability of HPV vaccines to usher in a discussion on human sexuality in a way consistent with their culture and values at a time when they determine their child is ready to receive that information, and to protect their children from potential harms, including cancer.

The American College of Pediatricians is a national medical association of licensed physicians and healthcare professionals who specialize in the care of infants, children, and adolescents. The mission of the College is to enable all children to reach their optimal, physical and emotional health and well-being.